Features
Seeing the Multiple Dimensions of Cancer:
How Targeted Imaging Technologies Are Bringing New Clarity to Cancer Care
Figure 2: Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) allows researchers to visualize entire circulatory systems, as with the mouse above, or the vasculature of tumors, making this technology an excellent tool for assessing anti-angiogenic therapies.
Because water is the main component of blood, the contrast agent makes anything containing significant amounts of blood, like blood vessels, shine brightly on the scans (Figure 2). "The angiogenic vessels in a tumor tend to be leaky, so they accumulate contrast agents rapidly and wash them out rapidly," said Choyke. "Measuring this ebb and flow of agent, DCE-MRI becomes a way of identifying feature and monitoring highly angiogenic tumors." This capability to directly image angiogenesis positions DCE-MRI well as a tool for assessing anti-angiogenic therapies. "To tell if non-antibody-based tyrosine kinase inhibitors or antibody based anti-angiogenics like bevacizumab are working," Choyke noted, "you need to be able to see the tumor and the drug's effect on the tumor over time. You need to know the tumor's angiogenic state before, during, and after treatment, and the closer you can get to gathering that information in real time, the better. With DCE-MRI, you can rapidly make those assessments."
Standard MRI takes a snapshot of a tumor's anatomy and location. By comparison, DCE-MRI is... dynamic, producing a representation of a tumor's blood flow over time.
The technique also provides greater flexibility for tumor diagnosis, staging, and screening. Choyke sees particular utility for the method in prostate cancer. "Prostate tumors are often hypervascular in comparison to the rest of the gland," said Choyke. "As an organ, the prostate is very challenging to image. It is located deep in the pelvis; it is an anatomically heterogeneous gland, and it is prone to hyperplastic changes that become more pronounced with age, the same age group that is at risk for prostate cancer. So, we are effectively trying to take a picture of an abnormality in a heterogeneous background in a small, remote organ."
There are additional reasons to have the tools available to image the prostate in detail. Prostate cancer tends to be localized, yet the majority of therapies are applied to the whole gland. "Ideally, we'd like to reduce the number of men undergoing whole gland therapies or radical prostatectomies, or we'd like to eliminate such therapies altogether and replace them with minimally invasive ablation techniques that could take care of the cancer without the side effects associated with more radical techniques."
Hypoxia in View
The translation of angiogenesis to oxygen concentration is not a one-to-one conversion. But knowledge of a tumor's oxygen level, or pO2, can be crucial when planning treatment or assessing the effectiveness of an investigational therapy. "Tumors with significant hypoxia, or low pO2, are very resistant to radiation therapy and maybe to chemotherapeutic agents as well," according to RBB Chief James Mitchell, Ph.D. "And for twenty years we have known that tumor hypoxia is directly tied to poor clinical outcomes, even in patients who undergo surgery."
"We have not had a readily available, noninvasive, and direct way to measure pO2," said Murali Cherukuri Krishna, Ph.D., Head of the RBB's Biophysical Spectroscopy Section. "Indirect radiological measurements only provide qualitative information. Direct measurements with oxygen-sensing electrodes are accurate but are invasive, inappropriate for many tumors, and only give a localized snapshot of tumor pO2."
"What we needed," Mitchell concluded, "was a quantitative method to map tumor hypoxia in deep sites in real time and in a way that can be coregistered with PET, MRI, or CT." Krishna and Mitchell's answer to this need is a new imaging modality called electron paramagnetic resonance imaging (EPRI), an offshoot of nuclear magnetic resonance (a technology widely used for chemical analysis) that allows direct, quantitative assessment of oxygenation across a whole tumor (Figure 3).
Several features of EPRI work in its favor as a viable technology. The method employs the same equipment used for MRI. "The radio frequency we use for EPRI can be generated with an MRI scanner," according to Krishna. "In one sitting, we can generate three-dimensional EPRI oxygen maps and MRI anatomic maps of the same tumor."
Figure 3: Integrating images generated using multiple techniques can provide very comprehensive information about a tumor. For instance, overlaying MRI and EPRI data lets researchers assess structure, blood fl ow, blood volume, metabolite levels, and oxygenation in mouse model of squamous cell carcinoma. (left leg, tumor; right leg, normal)
But its development did not come without challenges. "EPRI looks for free radicals," said Krishna. "The body, especially the immune system, makes a number of endogenous free radicals. But none of them are stable or spectrally simple enough to be used for imaging. To make this technology work, we needed an artificial free radical that could be used as a tracer, something that would interact directly with the oxygen in a tumor and produce a simple, detectable signal."
"GE has developed a family of tracers called TAM probes specifically for in vivo paramagnetic imaging," Mitchell noted. "Because the TAM signal on an EPRI scan increases linearly with oxygen concentration, imaging the tracer distribution within a tumor gives us a direct, quantitative, real-time image of its oxygen distribution."
Computational resources also proved to be a roadblock. "Paramagnetic signals last only one to two microseconds," Mitchell said. "The magnetic signals detected with MRI, by contrast, last about a second. The processing power needed to capture paramagnetic data simply hasn't been available until now."
Krishna and Mitchell—along with Postdoctoral Fellow Shingo Matsumoto, Ph.D., and Fuminori Hyodo, Ph.D., formerly a Postdoctoral Fellow in the Krishna laboratory and now at Kyushu University in Japan—published the results of a successful proof-of-concept mouse study in the April 2008 issue of the Journal of Clinical Investigation; the team is already pursuing translation to humans.
"With the ongoing development of technologies like DCE-MRI and EPRI, all here within the collaborative environment of CCR," Mitchell continued, "we now have the first real opportunity to look at tumor pO2, metabolism, blood flow, vascularity, and anatomy and make them all correspond. We can't yet tell what the full impact will be on drug development and clinical care, but as these imaging modalities mature, we can tell that they will change the playing field."
To Systematically Look Within
Angela Stuber (left), Certifi ed Nuclear Medicine Technologist, and Karen Kurdziel, M.D. (right), position their patient for a combined, single photon emission tomography/computed axial tomography scan (SPECT/CT scan).
Targeted imaging technologies such as dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) and electron paramagnetic resonance imaging (EPRI) are giving precise insight into how cancer works at a molecular level. While these developments have the potential to revolutionize standard clinical care, they are also fueling a paradigm shift in drug development.
To have this kind of R&D impact, though, dedicated equipment and resources need to be available. Time on scanning equipment used in clinical trials is limited, which constricts CCR’s ability to conduct early-phase translational drug development studies like exploratory clinical trials (small trials in which patients receive a trace dose of a developmental drug as a way of assessing whether the drug behaves in people as it does in preclinical models).
To bolster CCR’s capacity for these kinds of research studies, the Molecular Imaging Program (MIP), with NCI’s Developmental Therapeutics Program (DTP), opened the Molecular Imaging Clinic this past summer. "This facility is separate from the clinical facility," said Karen Kurdziel, M.D., a Staff Clinician with CCR and the Director of this new facility. "It is dedicated to drug discovery research protocols and lets us use imaging as a marker to make early go/no-go decisions in an exploratory context."
The new facility will house a comprehensive set of scanners, including PET, PET/CT, and 3T MRI, as well as full equipment for capturing vital signs and blood chemistry, all in close proximity. Together, this equipment will let MIP researchers and their colleagues from across NCI learn relatively quickly what a drug actually does. "We can take a drug, label it with an appropriate tag, and track it as it travels through the body," Kurdziel explained. "With this kind of information, we can see how much of a drug actually reaches the tumor and also where else it goes."
These studies can provide valuable insight into a drug’s mechanism of action and the biology underlying side effects. "We have already started a study of paclitaxel (Taxo®), which no one has ever studied using imaging," said Kurdziel. "Its pharmacokinetics have been studied using plasma, blood, and urine, but with PET imaging, we can visualize the realtime whole body drug distribution. We have already found that it migrates to the gut and stays there, attacking the rapidly dividing cells in the gut lining, which may help explain the gastrointestinal side effects associated with paclitaxel treatment.
"This technology," Kurdziel continued, "can be used to determine how much of a dose actually penetrates the tumor. With the emergence of molecularly targeted drug therapies, PET imaging can be used to determine the dose needed, which may be much lower than the maximum tolerable dose that we use currently."
Kurdziel notes that data like this can also be used to create standard imaging based markers to guide all cancer drug development. "If we can get the FDA to approve certain imaging markers as biomarkers, such as FDG for metabolism and FLT for proliferation, we can establish standard imaging endpoints that would allow drug developers to look for valid responses after weeks of treatment instead of years."
